tbuckley/cabot-search huggingface dataset:
A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis
Authors: John Mascarenhas, Anna Rita Migliaccio, Heidi Kosiorek, Rupali Bhave, Jeanne Palmer, Andrew Kuykendall, Ruben Mesa, Raajit K. Rampal, Aaron T. Gerds, Abdulraheem Yacoub, Kristen Pettit, Moshe Talpaz, Rami Komrokji, Marina Kremyanskaya, Agapito Gonzalez, Frank Fabris, Kathryn Johnson, Mikaela Dougherty, Erin McGovern, Juan Arango Ossa, Dylan Domenico, Noushin Farnoud, Rona Singer Weinberg, Amy Kong, Vesna Najfeld, Alessandro Maria Vannucchi, Francesca Arciprete, Maria Zingariello, Mario Falchi, Mohamed E. Salama, Carolyn Mead-Harvey, Amylou Dueck, Lilian Varricchio, Ronald Hoffman
Journal: Clinical Cancer Research (2023)

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F.We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF.No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells.AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.
Dual-Organ Transplantation: Indications, Evaluation, and Outcomes for Heart-Kidney and Heart-Liver Transplantation: A Scientific Statement From the American Heart Association
Authors: Michelle M. Kittleson, Kavita Sharma, Daniel C. Brennan, Xingxing S. Cheng, Sheryl L. Chow, Monica Colvin, Adam D. DeVore, Shannon M. Dunlay, Meg Fraser, Jacqueline Garonzik-Wang, Prateeti Khazanie, Kevin M. Korenblat, Duc T. Pham
Journal: Circulation (2023)

Although heart transplantation is the preferred therapy for appropriate patients with advanced heart failure, the presence of concomitant renal or hepatic dysfunction can pose a barrier to isolated heart transplantation. Because donor organ supply limits the availability of organ transplantation, appropriate allocation of this scarce resource is essential; thus, clear guidance for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation is urgently required. The purposes of this scientific statement are (1) to describe the impact of pretransplantation renal and hepatic dysfunction on posttransplantation outcomes; (2) to discuss the assessment of pretransplantation renal and hepatic dysfunction; (3) to provide an approach to patient selection for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation and posttransplantation management; and (4) to explore the ethics of multiorgan transplantation.
Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Laura Costas, Irene Onieva, Beatriz Pelegrina, Fátima Marin, Álvaro Carmona, Marta López-Querol, Jon Frias-Gomez, Paula Peremiquel-Trillas, José Manuel Martínez, Eduard Dorca, Joan Brunet, Marta Pineda, Jordi Ponce, Xavier Matias-Guiu, Silvia de Sanjosé, Francesc Xavier Bosch, Laia Alemany, Sonia Paytubi
Journal: Clinical Cancer Research (2023)

Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate patients with endometrial cancer from controls.Overall, 72 samples were analyzed using next-generation sequencing (NGS) with molecular identifiers targeting 47 genes. We evaluated urine supernatant samples from women with endometrial cancer (n = 19) and age-matched controls (n = 20). Cell pellets from urine and plasma samples from seven cases were sequenced; further, we also evaluated paired tumor samples from all cases. Finally, immunohistochemical markers for molecular profiling were evaluated in all tumor samples.Overall, we were able to identify mutations in DNA from urine supernatant samples in 100% of endometrial cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF) ≥ 2% in the urine supernatant samples. The molecular classification obtained by using tumor samples and urine samples showed good agreement. Analyses in paired samples revealed a higher number of mutations and VAF in urine supernatants than in urine cell pellets and blood samples.Evaluation of somatic mutations using urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and molecular classification. The diagnostic performance for endometrial cancer detection was very high, and cases could be molecularly classified using these noninvasive and self-collected samples. Additional multicenter evaluations using larger sample sizes are needed to validate the results and understand the potential of urine samples for the early detection and prognosis of endometrial cancer.
Overcoming the blood-brain barrier? - prediction of blood-brain permeability of hydrophobically modified polyethylenimine polyplexes for siRNA delivery into the brain with in vitro and in vivo models
Authors: Natascha Hartl, Bettina Gabold, Friederike Adams, Philipp Uhl, Sabrina Oerter, Sabine Gätzner, Marco Metzger, Ann-Christine König, Stefanie M. Hauck, Antje Appelt-Menzel, Walter Mier, Gert Fricker, Olivia M. Merkel
Journal: Journal of Controlled Release (2023)
Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages
Authors: Wei Yuan, Qian Zhang, Danling Gu, Chenfei Lu, Deobrat Dixit, Ryan C. Gimple, Yisu Gao, Jiancheng Gao, Daqi Li, Danyang Shan, Lang Hu, Lu Li, Yangqing Li, Shusheng Ci, Hao You, Linping Yan, Kexin Chen, Ningwei Zhao, Chuanhai Xu, Jianyun Lan, Dong Liu, Junxia Zhang, Zhumei Shi, Qiulian Wu, Kailin Yang, Linjie Zhao, Zhixin Qiu, Deguan Lv, Wei Gao, Hui Yang, Fan Lin, Qianghu Wang, Jianghong Man, Chaojun Li, Weiwei Tao, Sameer Agnihotri, Xu Qian, Stephen C. Mack, Nu Zhang, Yongping You, Jeremy N. Rich, Guan Sun, Xiuxing Wang
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state. Experimental Design: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. Results: We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2–JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule–based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Conclusions: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
Accuracy and applicability of periodontitis risk assessment tools: A critical appraisal
Authors: Roberto Farina, Rodrigo Lopez, Anna Simonelli, Leonardo Trombelli
Journal: Periodontology 2000 (2023)

Abstract Currently, periodontal risk assessment finds application at first visit (to identify individuals at high risk of either disease incidence, if still healthy, or disease progression, if already diseased) as well as at patient monitoring after active treatment and enrolment in a supportive periodontal care program. Although the current case definition of periodontitis embeds a prognostic determination (ie, periodontitis grade) that showed a predictive value for periodontitis‐related tooth loss, some limitations of periodontitis grade call for the implementation of different risk assessment tools in clinical practice. For some of these, significantly higher accuracy in predicting tooth loss during supportive periodontal care was reported compared with periodontitis grade. Validated periodontal risk assessment tools may be functional to obtain greater adherence to the suggested preventive and treatment protocols, improve oral hygiene performance, and tailor supportive periodontal care. Interestingly, periodontal risk can also be informative of the risk of peri‐implantitis in patients programmed for implant placement or rehabilitated with dental implants. A critical appraisal on the rationale behind risk assessment and the balance between the advantages and limitations of exercising risk assessment in periodontology is presented.
Philadelphia Beverage Tax and Association With Prices, Purchasing, and Individual-Level Substitution in a National Pharmacy Chain
Authors: Sophia V. Hua, Joshua Petimar, Nandita Mitra, Christina A. Roberto, Erica L. Kenney, Anne N. Thorndike, Eric B. Rimm, Kevin G. Volpp, Laura A. Gibson
Journal: JAMA Network Open (2023)

Taxes on sweetened beverages are being implemented around the globe; an understanding of these taxes on individual-level behavior is necessary.
Management of Down Syndrome–Associated Leukemias
Authors: Anupam Verma, Philip J. Lupo, Nirali N. Shah, Johann Hitzler, Karen R. Rabin
Journal: JAMA Oncology (2023)

Down syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS.
Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting
Authors: Sebastian Greppmair, Alexander Brinkmann, Anka Roehr, Otto Frey, Stefan Hagel, Christoph Dorn, Amélie Marsot, Ibrahim El-Haffaf, Michael Zoller, Thomas Saller, Johannes Zander, Lea Marie Schatz, Christina Scharf, Josef Briegel, Iris K. Minichmayr, Sebastian G. Wicha, Uwe Liebchen
Journal: Intensive Care Medicine (2023)

Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models.A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision.The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|median_all_models 45.1/67.5%; MAPEmedian_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models.The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM.
Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors
Authors: Claire Gallois, Matteo Landi, Julien Taieb, Marine Sroussi, Bahar Saberzadeh-Ardestani, Antoine Cazelles, Sara Lonardi, Francesca Bergamo, Rossana Intini, Giulia Maddalena, Filippo Pietrantonio, Francesca Corti, Margherita Ambrosini, Antonia Martinetti, Marco Maria Germani, Chiara Boccaccio, Guglielmo Vetere, Sophie Mouillet-Richard, Aurélien de Reynies, Frank A. Sinicrope, Chiara Cremolini, Pierre Laurent-Puig
Journal: Clinical Cancer Research (2023)

Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI.In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed.In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P < 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08-0.45; P < 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster.This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.
Association of Corticosteroids With Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma Treated With Nivolumab
Authors: Félix Lefort, Cécile Dalban, Marine Gross-Goupil, Brigitte Laguerre, Sylvie Chabaud, Bernard Escudier, Laurence Albiges
Journal: JAMA Oncology (2023)

This nonrandomized controlled trial ancillary study evaluates the survival outcomes associated with corticosteroid use during nivolumab treatment for patients with metastatic renal cell carcinoma.
Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product
Authors: Maria Dul, Mohammed Alali, Mahmoud Ameri, Matthew Douglas Burke, Christine M. Craig, Benjamin Paul Creelman, Lisa Dick, Ryan F. Donnelly, Michael N. Eakins, Collrane Frivold, Angus Harry Forster, Philippe-Alexandre Gilbert, Stefan Henke, Sebastien Henry, Desmond Hunt, Hayley Lewis, Howard I. Maibach, Jessica Joyce Mistilis, Jung-Hwan Park, Mark R. Prausnitz, David Kenneth Robinson, Carmen Amelia Rodriguez Hernandez, Charles Ross, Juyeop Shin, Tycho Joseph Speaker, Kevin Michael Taylor, Darin Zehrung, James C. Birchall, Courtney Jarrahian, Sion A. Coulman
Journal: Journal of Controlled Release (2023)

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.
Effect of Internet-Delivered Emotion Regulation Individual Therapy for Adolescents With Nonsuicidal Self-Injury Disorder
Authors: Johan Bjureberg, Olivia Ojala, Hugo Hesser, Henrike Häbel, Hanna Sahlin, Kim L. Gratz, Matthew T. Tull, Emma Claesdotter Knutsson, Erik Hedman-Lagerlöf, Brjánn Ljótsson, Clara Hellner
Journal: JAMA Network Open (2023)

Importance Nonsuicidal self-injury is prevalent in adolescence and associated with adverse clinical outcomes. Effective interventions that are brief, transportable, and scalable are lacking. Objective To test the hypotheses that an internet-delivered emotion regulation individual therapy for adolescents delivered adjunctive to treatment as usual is superior to treatment as usual only in reducing nonsuicidal self-injury and that improvements in emotion regulation mediate these treatment effects. Design, Setting, and Participants This 3-site, single-masked, randomized superiority trial enrolled participants from November 20, 2017, to April 9, 2020. Eligible participants were aged between 13 and 17 years and met diagnostic criteria for nonsuicidal self-injury disorder; they were enrolled as a mixed cohort of consecutive patients and volunteers. Parents participated in parallel to their children. The primary end point was at 1 month after treatment. Participants were followed up at 3 months posttreatment. Data collection ended in January 2021. Interventions Twelve weeks of therapist-guided, internet-delivered emotion regulation individual therapy delivered adjunctive to treatment as usual vs treatment as usual only. Main Outcomes and Measures Primary outcome was the youth version of the Deliberate Self-harm Inventory, both self-reported by participants prior to treatment, once every week during treatment, and for 4 weeks posttreatment, and clinician-rated by masked assessors prior to treatment and at 1 and 3 months posttreatment. Results A total of 166 adolescents (mean [SD] age, 15.0 [1.2] years; 154 [92.8%] female) were randomized to internet-delivered emotion regulation therapy plus treatment as usual (84 participants) or treatment as usual only (82 participants). The experimental intervention was superior to the control condition in reducing clinician-rated nonsuicidal self-injury (82% vs 47% reduction; incidence rate ratio, 0.34; 95% CI, 0.20-0.57) from pretreatment to 1-month posttreatment. These results were maintained at 3-month posttreatment. Improvements in emotion dysregulation mediated improvements in self-injury during treatment. Conclusions and Relevance In this randomized clinical trial, a 12-week, therapist-guided, internet-delivered emotion regulation therapy delivered adjunctive to treatment as usual was efficacious in reducing self-injury, and mediation analysis supported the theorized role of emotion regulation as the mechanism of change in this treatment. This treatment may increase availability of evidence-based psychological treatments for adolescents with nonsuicidal self-injury. Trial Registration ClinicalTrials.gov Identifier: NCT03353961